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Bladder Cancer
171
Histology
Transitional cell carcinoma is responsible for 90% of all bladder cancers. These type
of cells can be papillary and superficial (70–75%) or solid and invasive (20–25%).
Squamous cell cancers comprise 5–10% of all bladder cancers. They display a
nodular and infiltrative pattern, and constitute 70% of all bladder tumors in regions
where schistosomiasis is endemic, like Egypt.
Adenocarcinoma is a rare form and comprises 2% of all bladder tumor. Thirty to
thirty-five percent of them originate from the urachal region, and the rest are related
to bladder exstrophy and are of nonurachal origin.
Undifferentiated carcinomas have a high nucleus/cytoplasm ratio and generally form
cell layers or clusters. They behave like small cell cancers and have a poor
prognosis.
Sites of
involvement
Bladder tumors involve the posterior and lateral walls often and involve the superior
wall least often. Patients with bladder carcinoma also frequently have carcinomas in
other urinary tract sites.
Types of bladder
cancer
Single papillary cancers are the most common type (70%) and the least likely to
show infiltration.
Diffuse papillary growths with minimal invasion
Sessile cancers are often high grade and invasive.
Carcinoma in situ (CIS; flat intraepithelial growth) appears either the same as
normal mucosa or as a velvety red patch
Figure 2. Pelvic MRI and CT scan for a bladder cancer.
6. Pathology
Knowledge of the growth pattern and histology of bladder cancer is essential for
appropriate treatment decisions. Table-3 describes the histology, sites of evolvement and
types of bladder cancer.
Table 3. Types of bladder cancer
Gustavo Arruda Viani
172
CIS of the
bladder
Until 80% of patients with untreated CIS develop invasive bladder cancer within 10
years after diagnosis.
Low-grade
superficial
carcinomas
It has a better prognosis than CIS. Although the recurrence rate is 80%, 80% of
patients with these tumors survive 5 years. Invasive cancer develops in only 10% of
patients with superficial tumors, often in association with CIS. More than 80% of
patients with both superficial cancers and CIS develop invasive malignancies.
High-grade or
invasive tumors
It is associated with CIS in 85% of cases.
Squamous cell cancers and adenocarcinomas are usually high grade and have an
aggressive clinical behavior.
Other uncommon and very aggressive histologic variants include sarcomatoid
cancer, small cell carcinoma, and micropapillary tumors.
Mode of spread
Bladder cancers spread both by lymphatic channels and by the bloodstream.
High-grade lesions are more likely to metastasize. Of patients with distant
metastases, 30% do not have involvement of the draining lymph nodes.
Invasive bladder cancer grows directly into the wall of the bladder, then into
extravesicular fat, and finally into adjacent organs.
Lymph nodes commonly involved include internal iliac, obturator, external iliac, and
common iliac nodes
Reference
Epstein JI, Amin MB, Reuter VR, Mostofi FK. The World Health Organization/International
Society of Urological Pathology consensus classification of urothelial (transitional cell)
neoplasms of the urinary bladder. Bladder Consensus Conference Committee. Am J Surg
Pathol. 1998;22(12):1435.
7. Routes of Spread and Recurrence
The three major routes of spread/recurrence in bladder cancer are local extension, and
regional (lymphatic) and distant (hematogenous) metastases (table-4).
Table 4. Major routes of spread and recurrence for bladder cancer
Reference
Stein JP, Lieskovsky G, Cote R et al. Radical cystectomy in the treatment of invasive
bladder cancer: long-term results in 1,054 patients. J Clin Oncol. 2001;19:666–675
8. Staging
The tumor, node, and metastasis (TNM), and stage grouping systems as determined by
the American Joint Committee on Cancer (AJCC) are outlined in table-5.
Bladder Cancer
173
Primary tumor (T)
Regional lymph nodes (N)
Distant metastasis (M)
TX Primary tumor cannot be assessed
NX Regional lymph nodes
cannot be assessed
MX Distant metastasis cannot
be assessed
T0 No evidence of primary tumor
N0 No regional lymph node
metastasis
M0 No distant metastasis
Ta Noninvasive papillary tumor
N1 Single regional lymph node
metastasis in the true pelvis
(hypogastric, obturator, external
iliac, or presacral lymph node)
M1 Distant metastasis
Tis Carcinoma in situ, “flat tumor”
N2 Multiple regional lymph
node metastasis in the true pelvis
(hypogastric, obturator, external
iliac, or presacral lymph node)
T1 Tumor invades subepithelial
connective tissue
N3 Lymph node metastases to
the common iliac lymph nodes
T2 Tumor invades muscularis propria
T2a Tumor invades superficial
muscularis propria (inner half)
T2b Tumor invades deep muscularis
propria (outer half)
T3 Tumor invades perivesical tissue
T3a Microscopically
T3b Macroscopically (extravesicle
mass)
T4 Tumor invades any of the following:
prostatic stroma, seminal vesicles,
uterus, vagina, pelvic wall, abdominal
wall
T4a Tumor invades prostatic stroma,
uterus, vagina
T4b Tumor invades pelvic wall,
abdominal wall
Table 5. AJCC TNM classification of bladder cancer
Reference
Urinary bladder. In: AJCC Cancer Staging Manual, 7th, Springer, New York 2010. p.497.
• The clinical stage at diagnosis is the most important prognostic factor for bladder
cancer.
• Prognostic factors associated with a higher risk of intravesical recurrence post
transurethral resection includes high-grade disease, carcinoma in situ and multifocal
disease.
• Patients submitted to cystectomy can be divided according to the stage into organ-
confined disease (confined to the wall of bladder with negative nodes, pT2,N0)
versus extra-vesicular invasion with negative nodes (pT3-T4,N0) and patients with
metastatic disease to pelvic lymph nodes (pTany, N+).
9. Prognostic Factors
Gustavo Arruda Viani
174
Modality
Description
Transurethral
resection (TUR)
It is the cornerstone for treating and T staging newly diagnosed bladder neoplasia.
One or more TURBT procedures and follow-up cystoscopy are sufficient
treatment for most superficial tumors.
Segmental
resection
It is associated with a high risk for recurrence. Segmental resection can be
considered for tumors with the following characteristics: solitary, localized to the
bladder dome Not associated with areas of CIS sought by multiple biopsies of
urothelial mucosa.
Intravesical
instillations
Chemotherapeutic agents include thiotepa, mitomycin C, valrubicin, and
doxorubicin. Immunotherapy has consisted of bacillus Calmette-Guerin (BCG)
with or without IFN-α.
BCG is administered weekly for 6 weeks followed by maintenance administration
of shorter courses. Maintenance BCG has been shown to augment the effects of a
single 6-weekly course.
Mitomycin C is also given weekly at a dose of 40 mg each time. A single
instillation of mitomycin C immediately following TURBT has been shown to
dramatically decrease the risk of tumor recurrence.
• Factors that predict success of bladder preservation after chemoradiation are
performance of complete transurethral resection, presence of complete response,
solitary tumor, lack of ureteral obstruction, or hydronephrosis; T2 is better than T3.
Reference
Stein JP, Lieskovsky G, Cote R et al. Radical cystectomy in the treatment of invasive bladder
cancer: long-term results in 1,054 patients. J Clin Oncol. 2001;19:666–675
10. Treatment
10.1. Superficial Tumors
• Most of the bladder cancers (75%) are superficial at presentation. Treatment of
superficial bladder tumors consists of resection (TUR), intravesical chemotherapy or
immunotherapy, and in selected cases, cystectomy.
• Majority superficial tumors can be completely resected by TUR.
• The most important determinations to be made in regard to these tumors are the risk
for recurrence and the risk for progression to muscle-invasive disease.
• Most patients with superficial bladder tumors will experience recurrence within 5
years of diagnosis.
• Approximately 30% of these patients will progress to muscle-invasive disease.
• For patients at high risk of recurrence or progression, intravesical therapy may be
added to TUR to reduce these risks.
• For patients with refractory superficial disease or extremely high risk for progression,
cystectomy may be considered. Table-6 resumes the treatment options for patients
with superficial bladder cancer.
Table 6. Treatment options for superficial bladder cancer
Bladder Cancer
175
Modality
Description
BCG instillations are considered more effective in reducing the risks for
recurrence and progression, as compared with chemotherapy. BCG is also curative
for most patients with CIS.
Both chemotherapy and BCG are frequently associated with local side effects,
such as bladder irritability, and both can rarely induce systemic adverse reactions.
Of particular importance, systemic infection with BCG affects 5% of the cases and
may lead to significant morbidity.
Radical cystectomy
The standard treatment for invasive bladder cancer, includes excision of the
bladder, perivesical fat, and attached peritoneum. Men undergo removal of the
entire prostate and seminal vesicles; women undergo en bloc removal of the
uterus, adnexa, and cuff of the vagina. Lymphadenectomy is controversial; it
probably does not improve survival but adds little morbidity and provides
information for staging. Removal of >10 regional lymph nodes is associated with
improved survival.
RT
RT is an alternative to surgery for highly motivated patients who desire to retain
their bladder. These multiple modality treatment plans include aggressive TURBT,
RT, and chemotherapy and may end up in delayed cystectomy in up to 20% of
cases.
Preoperative RT is seldom used.
Postoperative radiation has no proved role in bladder cancer.
Study
Description
Madersbacher et
al (2006)
Retrospective cohort of patients undergoing pelvic lymphadenectomy and radical
cystectomy. All patients were staged N0, M0 preoperatively, and no patient
received neoadjuvant radio/chemotherapy.
507 patients (age 66 +/- 12 years) with a mean follow-up time of 45 months (range,
0.1 to 176 months) were analyzed.
References
Shelley MD, Court JB, Kynaston H, Wilt TJ, Fish RG, Mason M. Intravesical Bacillus
Calmette-Guerin in Ta and T1 Bladder Cancer. Cochrane Database Syst Rev. 2000;
Sylvester RJ, Oosterlinck W, van der Meijden AP. A single immediate postoperative
instillation of chemotherapy decreases the risk of recurrence in patients with stage Ta T1
bladder cancer: a meta-analysis of published results of randomized clinical trials. J Urol.
2004;171(6 Pt 1):2186.
Treatment of Muscle Invasive Bladder Cancer
• Radical cystectomy is considered the standard treatment for patients with muscle-
invasive bladder cancer.
• Radical cystectomy is well indicated for patients with T2 tumours or higher and BCG
refractory nonmuscle invasive bladder cancer. Actually the best option is cystectomy
and urinary diversion. Lymphadenectomy is also performed and provides a small
survival advantage. The most commonly performed urinary diversions are the
creation of a orthotopic neobladder or ileal conduit. Diversion type is based on
patient preference and other patient factors, such as age and previous surgery or
radiotherapy (table-7).
Table 7. Clinical evidence for radical cystectomy in invasive bladder cancer
Gustavo Arruda Viani
176
Study
Description
Five-year DFS and OS were, respectively, 73% and 62% for patients with organ-
confined, lymph node-negative tumors (n = 217;<or = pT2, pN0) and 56% and 49%
for non-organ-confined, lymph node-negative tumors (n = 166;>pT2, pN0).
Distant metastases developed in 25% of patients with organ-confined tumors, 37%
with non-organ-confined tumors, and 51% with positive lymph nodes.
Stein et al
(2001)
Retrospective cohort of patients undergoing radical cystectomy with bilateral pelvic
iliac lymphadenectomy, with or without adjuvant radiation or chemotherapy.
1,054 patients (843 men [80%]and 211 women) with a median age of 66 years
(range, 22 to 93 years) were uniformly treated. Median follow-up was 10.2 years
(range, 0 to 28 years).
DFS at 5 and 10 years for the entire cohort was 68% and 66%, respectively. The 5-
and 10-year DFS for patients with organ-confined, lymph node-negative tumors was
92% and 86% for P0 disease, 91% and 89% for Pis, 79% and 74% for Pa, and 83%
and 78% for P1 tumors, respectively.
Patients with muscle invasive (P2 and P3a), lymph node-negative tumors had 89%
and 87% and 78% and 76% 5- and 10-year DFS, respectively.
Patients with nonorgan-confined (P3b, P4), lymph node-negative tumors
demonstrated a significantly higher probability of recurrence compared with those
with organ-confined bladder cancers (P<.001). The 5- and 10-year DFS for P3b
tumors was 62% and 61%, and for P4 tumors was 50% and 45%, respectively
involvement (P<.001).
Hautmann et al
(2006)
Retrospective cohort of patients undergoing radical cystectomy with pelvic lymph
node dissection for transitional cell carcinoma of the bladder. Patients with
neoadjuvant radiotherapy/chemotherapy were excluded.
A total of 788 patients with a mean age +/- SD of 65 +/- 10 years and a mean
followup of 53.5 months.
A neobladder was constructed in 75.4% of patients.
10-year DFS and OS rates were 59.1% and 44.9%, respectively. Positive lymph
nodes were present in 143 patients (18%). The rate of DFS at 5 years was 82.5% for
pT2a pN0, 61.9% for pT2b and pT3a pN0, and 53.1% for pT3b pN0disease.
Local and distant failure rates were 4% and 9.5% for organ confined tumors, 15.9%
and 19.2% for nonorgan confined tumors, and 20.4% and 45.1% in patients with
positive lymph nodes, respectively.
Table 7. (Continued)
References
Madersbacher S, Hochreiter W, Burkhard F, Thalmann GN, Danuser H, Markwalder R,
Studer UE. Radical cystectomy for bladder cancer today--a homogeneous series without
neoadjuvant therapy. J Clin Oncol. 2003;21(4):690.
Stein JP, Lieskovsky G, Cote R, Groshen S, Feng AC, Boyd S, Skinner E, Bochner B,
Thangathurai D, Mikhail M, Raghavan D, Skinner DG Radical cystectomy in the
treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol.
2001;19(3):666.
Hautmann RE, Gschwend JE, de Petriconi RC, Kron M, Volkmer BG. Cystectomy for
transitional cell carcinoma of the bladder: results of a surgery only series in the
neobladder era. J Urol. 2006;176(2):486.
Bladder Cancer
177
Advanced Bladder
Cancer Metaanalysis (2003)
Uptodate data of 2688 individual patients from ten available randomised
trials.
Platinum-based combination chemotherapy showed a significant benefit to
overall survival (13% reduction in risk of death; 5% absolute benefit at 5
years).
This effect was observed irrespective of the type of local treatment, and did
not vary between subgroups of patients.
Although platinum based combination chemotherapy was beneficial, there
was no evidence to support the use of single-agent platinum.
Skinner et al.
(1991)
91 patients with deeply invasive, pathological stage P3, P4 or N+ were
randomized to adjuvant chemotherapy or to observation after radical
cystectomy and pelvic lymph node dissection.
Chemotherapy was planned as 4 courses at 28-day intervals of 100 mg./M.2
cisplatin, 60 mg./M.2 doxorubicin and 600 mg./M.2 cyclophosphamide.
A significant delay was shown in the time to progression (p = 0.0010) with
70% of the patients assigned to chemotherapy free of disease at 3 years
compared to 46% in the observation group.
Median survival time for patients in the chemotherapy group was 4.3 years
compared to 2.4 years in the observation group (p = 0.0062).
Paz-Ares et al
(2010)
Randomized 340 patients with bladder cancer either to four cycles
of paclitaxel, gemcitabine, and cisplatin or to observation before surgery. The
study was terminated in 2007 because of poor accrual after 142 patients had
been enrolled.
At a median follow-up of 51 months, there was a statistically significant
increase in overall survival with chemotherapy compared to observation
(5year- OS 60 versus 30 %) 0.44).
• Patients with T3 or higher tumors should be treated with neoadjuvant cisplatin-based
chemotherapy, followed by radical cystectomy. On the other hand, patients who do
not receive neoadjuvant chemotherapy but have perivesical tumor extension (stage
T3 or higher) or regional lymph node involvement should receive adjuvant
chemotherapy (table-8).
Table 8. Clinical evidence for neoadjuuvant or adjuvant chemotherapy in invasive
bladder cancer
References
Advanced Bladder Cancer Meta-analysis Collaboration. Neoadjuvant chemotherapy in
invasive bladder cancer: a systematic review and meta-analysis. Lancet. 2003;361
(9373):1927.
Skinner DG, Daniels JR, Russell CA, Lieskovsky G, Boyd SD, Nichols P, Kern W, Sakamoto
J, Krailo M, Groshen S. The role of adjuvant chemotherapy following cystectomy for
invasive bladder cancer: a prospective comparative trial. J Urol. 1991;145(3):459.
Paz-Ares LG, Solsona E, Esteban E, et al. Randomized phase III trial comparing adjuvante
paclitaxel/gemcitabine/cisplatin (PGC) to observation in patients with resected invasive
bladder cancer: Results of the Spanish Oncology Genitourinary Group (SOGUG) 99/01
study (abstract #LBA4518). J Clin Oncol 2010; 28:18s.
Gustavo Arruda Viani
178
Study
Description
Shipley et al. (1998)
123 patients with clinical stage T2 to T4aNXMO bladder cancer were
randomized to receive (arm 1, n=61 ) two cycles of MCV before 39.6-Gy pelvic
irradiation with concurrent cisplatin 100 mg/m2 for two courses 3 weeks apart.
Patients in the arm 2 (n=62) did not receive MCV before concurrent cisplatin
and radiation therapy. The CR patients were treated with an additional 25.2 Gy
to a total of 64.8 Gy and one additional dose of cisplatin. Those with less than a
CR underwent cystectomy. The median follow-up of all patients who survived is
60 months.
The 5-year OS rate was 49%; 48% in arm 1 and 49% in arm 2. 35% of the
patients had evidence of distant metastases at 5 years; 33% in arm 1 and 39% in
arm 2.
The 5-year OS rate with a functioning bladder was 38%, 36% in arm 1 and 40%
in arm 2. None of these differences are statistically significant.
Rodel et al. (2002)
415 patients with bladder cancer (high-risk T1, n = 89; T2 to T4, n = 326) were
treated with radiotherapy (RT; n = 126) or radiochemotherapy (RCT; n = 289)
after transurethral resection (TUR) of the tumor. In case of persistent or
recurrent invasive tumor, salvage-cystectomy was recommended. Median
follow-up was 60 months (range, 6 to 199 months).
CR was achieved in 72% of patients. Local control after CR without muscle-
invasive relapse was maintained in 64% of patients at 10 years.
Distant metastases were diagnosed in 98 patients with an actuarial rate of 35% at
10 years. 10 year DFS was 42%, and more than 80% of survivors preserved their
bladder. Early tumor stage and a complete TUR were the most important factors
predicting CR and survival.
RCT was more effective than RT alone in terms of CR and survival. Salvage
cystectomy for local failure was associated with a 45% DFS rate at 10 years.
Cystectomy because of a contracted bladder was restricted to 2% of patients.
Tester et al. (1993)
Patients with invasive bladder cancer, clinical Stages T2-4, NO-2 or NX, MO
were treated with pelvic radiotherapy 40 Gy in 4 weeks and cisplatin 100 mg/m2
on days 1 and 22. Complete responders were given an additional 24 Gy bladder
boost plus a third dose of cisplatin; patients with residual tumor after 40 Gy were
assigned radical cystectomy.
CR following cisplatin and 40 Gy for evaluable cases was 31/47 (66%). Acute
toxicity was acceptable with only two patients not completing induction therapy.
Patients with poorly differentiated tumors were more likely to achieve complete
remission. Of fully evaluable patients, 28/42 (67%) achieved complete remission
with induction therapy, 11 remain continuously in remission, and eight have
relapsed with bladder as the only site of failure. Median survival is not reached,
with 17/42 (19/48) deaths reported. Actuarial survival is 64% at 3 years.
• Bladder preservation is an alternative approach for carefully selected patients.
Options include chemoradiation, radical transurethral resection, and partial
cystectomy. All these modalities have significant advantages in terms of healthrelated quality of life. But incertains about their equivalence in terms of local control
has not been established.
• Among these strategies radiotherapy concurrent with cisplatin-based chemotherapy is
the most used to bladder preservation , mainly, in patients who are medically unfit
for cystectomy or who refuse cystectomy (table-9).
Table 9. Clinical evidence for chemoradiation in invasive bladder cancer
Bladder Cancer
179
References
Shipley WU, Winter KA, Kaufman DS, Lee WR, Heney NM, Tester WR, Donnelly BJ,
Venner PM, Perez CA, Murray KJ, Doggett RS, True LD. Phase III trial of neoadjuvant
chemotherapy in patients with invasive bladder cancer treated with selective bladder
preservation by combined radiation therapy and chemotherapy: initial results of Radiation
Therapy Oncology Group 89-03. J Clin Oncol. 1998;16(11):3576.
Rödel C, Grabenbauer GG, Kühn R, Papadopoulos T, Dunst J, Meyer M, Schrott KM, Sauer
R. Combined-modality treatment and selective organ preservation in invasive bladder
cancer: long-term results. J Clin Oncol. 2002;20(14):3061.
Tester W, Porter A, Asbell S, Coughlin C, Heaney J, Krall J, Martz K, Venner P, Hammond
E. Combined modality program with possible organ preservation for invasive bladder
carcinoma: results of RTOG protocol 85-12. Int J Radiat Oncol Biol Phys. 1993;25
(5):783.
11. Radiotherapy Technique
A CT scan is performed with the patient supine in the treatment position with arms folded
across the chest with ankle supports to stabilise the legs and pelvis, and a knee support for
comfort. The bladder should be emptied immediately before scanning and treatment, to
reduce the volume irradiated and doses to normal tissues. A small volume of oral contrast is
given 1 h before the planning CT scan to show the small bowel. The scan is performed with 5
mm slices from the lower border of L5 to the inferior border of the ischial tuberosities. An
anterior tattoo is placed over the pubic symphysis and two lateral tattoos to prevent lateral
rotation with radio-opaque markers used for location on the scan. It is important to confirm on
the planning scan that the patient has been able to empty the bladder. MRI is beneficial in
planning partial but not whole bladder treatments and MRI/CT fusion may be useful.
The GTV is difficult to define on CT alone, but MRI/CT fusion may help. In patients
with tumours at the bladder base, the proximal urethra and in men the prostate and prostatic
urethra are included on the CTV. The PTV is the CTV with a 1.5–2 cm margin (figure-3).
Studies have shown that the most significant bladder movement is in the cranial and AP
directions. Bladder movement has been shown to occur in up to 60 % of patients as a
displacement of over 1.5 cm between the bladder wall and the 95 per cent isodose. It is
reasonable therefore to grow the CTV by 1.5 cm to form the PTV around the normal outside
bladder wall, but to grow the CTV by 2 cm to form the PTV around the primary bladder
tumour and any extravesical spread. OAR should be outlined including rectum, femoral heads
and small bowel. Recommended dose constraints are: rectum V50 < 60 per cent, V60 < 50
per cent; femoral heads V50 < 50 per cent; small bowel V45 < 250 cm3. For palliation of T4
tumours and pelvic nodal disease, the PTV must include the primary disease and its extension
into the pelvis. If this volume is excessively large it can be reduced to cover only the area
causing symptoms.
Gustavo Arruda Viani
180
Figure 3. Planning CT for bladder outlined.
Figure 4. Isodose lines distribution for three fields conformal technique.
The potential for radiation therapy to eradicate bladder cancer has probably been limited
over the years by technologic factors that prevented the accurate and reproducible delivery of
radiation at sufficient doses to the primary tumor and pelvic lymph nodes while
simultaneously sparing important adjacent normal tissues and minimizing toxicity.
Advances in radiation therapy planning and delivery have the potential to overcome these
limitations, thereby improving the likelihood of curing bladder cancer while preserving